Many extracellular signals, such as light, growth factors, cytokines and chemical or physical stresses, activate multi-tiered kinase cascades in the cytoplasm of cells. For example, a growth factor such as epidermal growth factor (EGF) will bind to its cognate receptor on the cell surface, thereby activating the intercellular protein ras, which is associated with the cytoplasmic portion of the cell surface receptor. Ras phosphorylates and thereby activates raf1, a mitogen-activated protein kinase kinase kinase (MAPKKK). Raf1 then induces (also by phosphorylation) the activation of mitogen-activated protein kinase kinases (MEKs), which in turn phosphorylate extracellular signal regulated kinases (ERKs). When phosphorylated, ERKs translocate to the nucleus where they phosphorylate and thus activate transcription factors such as stress activated protein kinase 1 (SAP1) and ternary complex factor Elk1. See, e.g., Fanger et al., 1997, Current Opin. Genet. Dev. 7:67-74.
Stress (such as heat and ultraviolet (UV) light) and cytokines (such as TNF- and IL-1) activate their own sets of kinase-kinase-kinases, termed JNKKKs. These, in turn, act on specific JNKKs, which activate c-Jun-N terminal kinase (JNK) and p38. The last two kinases enter the nucleus, where they phosphorylate and activate transcription factors. See, e.g., Diene et al., 1997, PNAS 94:9687-92.
Most of the initial events in the cellular responses to different stresses have not been elucidated so far. However, it is clear that different extracellular signals activate different members of the JNKKK family. Thus, some JNKKKs are specifically responsive to TNF-α, others to osmotic shock, yet others to UV illumination. Diene et al., 1997, above; Raingeaud et al., 1995, J. Biol. Chem. 270:7420-6.
Skin cells such as keratinocytes are particularly susceptible to ultraviolet radiation damage. However, very little is known about how keratinocytes respond to ultraviolet radiation stress. Manipulation of keratinocyte responses to environmental stress could result in therapies for a wide variety of skin disorders, as well as cosmetic uses.
Therefore, there is a great need in the art to elucidate the components involved in keratinocyte signal transduction that can be used as targets for drug screening. Accordingly, this invention provides several novel JNKKKs expressed by keratinocytes and involved in the cellular response to ultraviolet radiation, and uses thereof.